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Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults

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Abstract

Autosomal recessive CARD9 deficiency underlies life-threatening, invasive fungal infections in otherwise healthy individuals normally resistant to other infectious agents. In less than 10 years, 58 patients from 39 kindreds have been reported in 14 countries from four continents. The patients are homozygous (n = 49; 31 kindreds) or compound heterozygous (n = 9; 8 kindreds) for 22 different CARD9 mutations. Six mutations are recurrent, probably due to founder effects. Paradoxically, none of the mutant alleles has been experimentally demonstrated to be loss-of-function. CARD9 is expressed principally in myeloid cells, downstream from C-type lectin receptors that can recognize fungal components. Patients with CARD9 deficiency present impaired cytokine and chemokine production by macrophages, dendritic cells, and peripheral blood mononuclear cells and defective killing of some fungi by neutrophils in vitro. Neutrophil recruitment to sites of infection is impaired in vivo. The proportion of Th17 cells is low in most, but not all, patients tested. Up to 52 patients suffering from invasive fungal diseases (IFD) have been reported, with ages at onset of 3.5 to 52 years. Twenty of these patients also displayed superficial fungal infections. Six patients had only mucocutaneous candidiasis or superficial dermatophytosis at their last follow-up visit, at the age of 19 to 50 years. Remarkably, for 50 of the 52 patients with IFD, a single fungus was involved; only two patients had IFDs due to two different fungi. IFD recurred in 44 of 45 patients who responded to treatment, and a different fungal infection occurred in the remaining patient. Ten patients died from IFD, between the ages of 12 and 39 years, whereas another patient died at the age of 91 years, from an unrelated cause. At the most recent scheduled follow-up visit, 81% of the patients were still alive and aged from 6.5 to 75 years. Strikingly, all the causal fungi belonged to the phylum Ascomycota: commensal Candida and saprophytic Trychophyton, Aspergillus, Phialophora, Exophiala, Corynesprora, Aureobasidium, and Ochroconis. Human CARD9 is essential for protective systemic immunity to a subset of fungi from this phylum but seems to be otherwise redundant. Previously healthy patients with unexplained invasive fungal infection, at any age, should be tested for inherited CARD9 deficiency.

Key Points

• Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state.

• CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands.

• Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein).

• The functional impacts of CARD9 mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity.

• The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular) Candida infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis.

• The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned.

• Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease.

• All patients with unexplained IFD should be tested for CARD9 mutations. Familial screening and genetic counseling should be proposed.

• The treatment of patients with CARD9 mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing Candida infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.

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Acknowledgments

We thank all members of the Laboratory of Human Genetics of Infectious Diseases from the Necker and Rockefeller branches and, in particular, Yelena Nemirovskaya and Cécile Patissier for administrative work, Peng Zhang and Yuval Itan for helpful discussions, and Mélanie Migaud for technical work. We also warmly thank Dr. Fanny Lanternier and Prof. Olivier Lotholary, and Prof. Davood Mansouri (Masih Daneshvari Hospital, Tehran, Iran) for his collaboration and follow-up of patients.

Funding

This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, Assistance publique - Hôpitaux de Paris (AP-HP), the Rockefeller University, the St. Giles Foundation, and grants from Agence Nationale pour la Recherche (ANR) (grant HGDIFD no. ANR-14-CE15-0006-01, grant EURO-CMC no. ANR-14-RARE-0005-02) and from the National Institutes of Health (NIH) (R01-AI-127564). This study also received funding from the ANR as part of the “Investments for the Future” program (grant number ANR-10-IAHU-01) and Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (grant no. ANR-10-LABX-62-IBEID). AP was supported an AP-HP interface contract. EC was supported by the Belgian Fond National de la Recherche Scientifique (F.N.R.S).

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Authors and Affiliations

  1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015, Paris, France

    Emilie Corvilain, Jean-Laurent Casanova & Anne Puel

  2. Imagine Institute, Paris Descartes University, 75015, Paris, France

    Emilie Corvilain, Jean-Laurent Casanova & Anne Puel

  3. Free University of Brussels, Brussels, Belgium

    Emilie Corvilain

  4. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Jean-Laurent Casanova & Anne Puel

  5. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015, Paris, France

    Jean-Laurent Casanova

  6. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

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  1. Emilie Corvilain
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Correspondence to Anne Puel.

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Corvilain, E., Casanova, JL. & Puel, A. Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults. J Clin Immunol 38, 656–693 (2018). https://doi.org/10.1007/s10875-018-0539-2

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